Fibrinogen is a glycoprotein present as a normal component of blood plasma. It participates in platelet aggregation and fibrin formulation in the blood clotting mechanism.
Platelets are cellular elements found in whole blood which also participate in blood coagulation. Fibrinogen binding to platelets is important to normal platelet function in the blood coagulation mechanism. When a blood vessel receives an injury, the platelets binding to fibrinogen will initiate aggregation and form a thrombus. Interaction of fibrinogen with platelets occurs through a membrane glycoprotein complex, known as GP IIb/IIIa; this is an important feature of the platelet function. Inhibitors of this interaction are useful in modulating platelet thrombus formation.
It is also known that another large glycoprotein named fibronectin, which is a major extracellular matrix protein, interacts with platelets. Various relatively large polypeptide fragments in the cell-binding domain of fibronectin have been found to have cell-attachment activity. Certain relatively short peptide fragments from the same molecule were found to promote cell attachment to a substrate when immobilized on the substrate or to inhibit attachment when in a solubilized or suspended form.
U.S. Pat. No. 5,721,366 is directed to a class of compounds of the formula ##STR4## which are useful as modulators and/or inhibitors of platelet aggregation. Included in this class of compounds is a compound of the formula ##STR5## generically known as orbofiban, chemically known as N-[[[1-[4-(aminoiminomethyl)phenyl]-2-oxopyrrolidin-3S-yl]amino]carbonyl]- .beta.-alanine.
U.S. Pat. No. 5,610,296 discloses compounds of the formula ##STR6## wherein R.sub.1 is selected from the group consisting of H, lower alkyl, and aryl; and
wherein R.sub.6 is selected from the group consisting of lower alkyl, aryl, arylalkyl and acyloxymethyl.
U.S. Pat. No. 5,344,957 is directed to GP IIb/IIIa antagonists of the formula ##STR7## which are useful as modulators and/or inhibitors of platelet aggregation. Included in this class of compounds is a compound of the formula ##STR8## generically known as xemilofiban and chemically known as ethyl 3S-[[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4-pentyno ate.
Bioconversion of amidoxime prodrugs to amidines has been disclosed and occurs via hepatic metabolism [Hauptmann, J. et al. Pharmazie 43, 559-560 (1988)]. European Patent Application 656,348 A2 discloses double prodrugs of a series of glycoprotein IIb/IIIa antagonists. The compounds are further disclosed in Weller, T. et al. J. Med. Chem. 39, 3139-3147 (1996).